The above-mentioned compound, whose structural formula is set forth below,
is a known active ingredient, also known as “citalopram”, which is used for preparing pharmaceutical compositions intended for the treatment of depression.
Citalopram was described for the first time in Belgian patent application BE850401 (and in corresponding U.S. Pat. No. 4,136,193). A number of patent documents further relate to methods for its preparation.
With a chiral center, citalopram is generally produced and marketed in the form of a racemic mixture. As set forth in EP347066, the S(+) enantiomer, better known as escitalopram, is responsible for essentially the entire pharmacological activity of racemic citalopram. European patent application EP347066 describes two methods for preparing escitalopram.
The first method begins with racemic 4-(4-dimethylamino)-1-(4′-fluorophenyl)-1-(hydroxybutyl)-3-(hydroxymethyl)benzonitrile, which is subsequently esterified with an enantiomerically active acyl chloride, such as (+) or (−)-α-methoxy-α-trifluoromethylphenylacetyl chloride. From each (+) and (−) acyl chloride, two diastereoisomeric esters, which are separated by means of high performance liquid chromatography (“HPLC”), are obtained. The resulting enantiomerically pure ester, and subsequent cyclization in the presence of potassium t-butoxide in toluene, allows for the isolation of the pure enantiomer of citalopram from each ester.
The second method begins with enantiomerically pure 4-(4-dimethylamino)-1-(4′-fluorophenyl)-1-(hydroxybutyl)-3-(hydroxymethyl)benzonitrile (for example, (+)). In order to obtain this enantiomerically pure product, the amine is salified with an enantiomerically active acid, such as, for example, tartaric acid, in order to provide two diastereoisomeric salts which can be separated by crystallization. The pure enantiomer which is released from its salt is esterified to form a particularly labile ester (for example, with methane sulphonyl chloride) which, with the use of strong organic bases (for example, triethylamine), allows enantiomerically pure citalopram to be obtained.
Other methods for preparing escitalopram are described, for example, in U.S. Pat. No. 6,365,747, in U.S. patent application Ser No. US2003/0060641, and in international patent applications WO03/000672, WO03/006449 and WO03/051861.
The above-described methods are, however, characterized by the use of enantiomerically active acids and/or diastereoisomeric separations by crystallization or by means of HPLC, which set limits in terms of scalability of the process and reaction yields.